BACKGROUND: Progression-free survival (PFS) has not been extensively investigated as a surrogate for survival in the first-line treatments of pancreatic cancer. The aim of this review was to evaluate PFS as a potential surrogate endpoint for overall survival (OS) in advanced pancreatic cancer in trials comparing poly-chemotherapy to gemcitabine alone.
DATA SOURCES: A systematic literature search in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted. The key words included randomized trial, first-line chemotherapy, pancreatic cancer, gemcitabine and poly-chemotherapy. Adjusted weighted linear regression was used to calculate R_S (Spearman's rank-order correlation coefficient) between PFS and post-progression survival (PPS) with OS (R_S) and between treatment effects on PFS and OS (R_HR).
RESULTS: A total of 30 trials including 8467 patients met the inclusion criteria. Correlation between the treatment effects on PFS and OS (R_HR=0.78) and between the endpoint PFS and OS was high across all studies (R_S=0.75). The slope of the regression line was 0.76±0.26, indicating that an agent producing a 10% risk reduction for PFS will provide a 7.6%±2.6% risk reduction for OS. Correlation between PPS and OS was very strong (R_S=0.71) and accounted for more than 50% of the whole OS variability (R²=0.57).
CONCLUSION: Because of the robust correlation with OS and the potential influence of PPS caused by the second line therapies, it may be justified to consider PFS as a surrogate endpoint in trials evaluating new cytotoxic agents when gemcitabine is the control arm.

BACKGROUND: The role of diabetes mellitus (DM) in pancreatic fistula (PF) or clinical relevant PF (CR-PF) after pancreaticoduodenectomy (PD) or pylorus-preserving pancreaticoduodenectomy (PPPD) is unclear. We conducted a meta-analysis to investigate the relationship between DM and PF or CR-PF.
DATA SOURCES: Embase, MEDLINE and Cochrane databases were searched systematically for relevant articles from January 2005 to June 2013. The selected studies that examined clinical risk factors of PF or CR-PF were included. We created pooled estimates for our outcomes using the random-effects model.
RESULTS: Sixteen observational clinical studies were included. Pooling of PF rates from ten studies revealed that DM was associated with a decreased risk of PF (P=0.01). CR-PF rates from 8 studies showed no significant difference between DM and control group (P=0.14).
CONCLUSIONS: DM is not a risk factor for PF in patients undergoing PD or PPPD. On the contrary, patients without DM are at a higher risk of PF because the pancreases in these patients have more fatty tissue and the pancreas is soft.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD.
DATA SOURCE: We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed.
RESULTS: The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor γ expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy.
CONCLUSION: Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

BACKGROUND: Liver transplantation is the optimal treatment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma (HCC). Despite the strict selection of candidates, post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC. The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation.
DATA SOURCES: Relevant articles were identified by extensive searching of PubMed using the keywords "hepatocellular carcinoma", "recurrence" and "liver transplantation" between January 1996 and January 2014. Additional papers were searched manually from the references in key articles.
RESULTS: The current theories of HCC recurrence after liver transplantation are: (i) the growth of pre-transplant occult metastases; (ii) the engraftment of circulating tumor cells released at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, transarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes systemic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to clear the occult HCC cells after transplantation.
CONCLUSIONS: Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be directed towards combining multidisciplinary approaches and various treatment modalities.

BACKGROUND: The right lobe of the liver is generally preferred for living donor liver transplantation in adult patients with end-stage liver disease. It is important to know the preoperative factors relating to the major postoperative complications. We therefore evaluated the possible risk factors for predicting postoperative complications in right lobe liver donors.
METHODS: Data from 378 donors who had undergone right lobe hepatectomy at our center were evaluated retrospectively. The factors we evaluated included donor age, gender, body mass index (BMI), remnant liver volume, operation time, history of previous abdominal surgery, inclusion of the middle hepatic vein and variations in the portal and bile systems.
RESULTS: Of the 378 donors, 219 were male and 159 female. None of the donors died, but 124 (32.8%) donors experienced complications including major complications (Clavien scores III and IV) in 27 (7.1%). Univariate analysis showed that complications were significantly associated with male gender and higher BMI (P<0.05), but not with donor age, remnant liver volume, operation time, graft with middle hepatic vein, variations in the portal and bile systems and previous abdominal surgery (P>0.05). Multivariate logistic regression analysis showed that major complications were significantly associated with male gender (P=0.005) and higher BMI (P=0.029). Moreover, the Chi-square test showed that there were significant relationships between major complications and male gender (P=0.010, χ2=6.614, df=1) and BMI >25 kg/m2 (P=0.031, χ2=8.562, df=1). Of the 96 male donors with BMI >25 kg/m2, 14 (14.6%) with major complications had significantly smaller mean remnant liver volume than those (82, 85.4%) without major complications (32.50%±4.45% vs 34.63%±3.11%, P=0.029).
CONCLUSION: Male donors with BMI >25 kg/m2 and a remnant liver volume ≤32.50% had a significantly increased risk for major complications.

BACKGROUND: Glypican-3 (GPC-3) is frequently overexpressed in hepatocellular carcinoma (HCC). Recent studies have shown that GPC-3 is a highly efficient diagnostic biomarker of HCC and an indicator of poor prognosis in HCC patients who have undergone hepatectomy. However, its prognostic value in patients with HBV-associated HCC after liver transplantation (LT) is not clear. The present study is to evaluate the prognostic value of GPC-3 in patients with HBV-associated HCC after LT.
METHODS: A cohort of 104 HCC patients with HBV-associated cirrhosis who had undergone LT at our hospital between 2002 and 2011 were enrolled in this study. Samples of HCC were taken from these patients. GPC-3 protein expression was detected in paraffin-embedded specimens using immunohistochemistry. All related clinical data were obtained from the China Liver Transplant Registry. The relationship between GPC-3 expression and clinicopathological parameters was analyzed. Univariate and multivariate Cox-regression analyses were used to identify risk factors for poor prognosis.
RESULTS: GPC-3 was expressed in samples from 74 (71.2%) of the 104 patients. GPC-3 was expressed only in HCC cells. Positive staining was correlated with tumor size (P=0.004), encapsulation (P=0.018), pathological stage (P=0.027), portal vein invasion (P=0.043), tumor differentiation (P=0.002) and the Milan criteria (P=0.016). The 5-year survival rate and disease-free survival rate of patients with GPC-3-positive were lower than those (38.2% vs 75.4%, P<0.001; 30.8% vs 69.7%, P=0.001) of patients with GPC-3-negative. Multivariate Cox-regression analysis revealed that GPC-3 was an independent risk factor for 5-year survival rate (P=0.031) and disease-free survival rate (P=0.047), together with tumor differentiation, Milan criteria and pre-operative alpha-fetoprotein.
CONCLUSION: GPC-3 is a potential biomarker for poor prognosis after LT in HCC patients with HBV-associated cirrhosis.

BACKGROUND: The current methods used for diagnosing hepatocellular carcinoma (HCC) are unsatisfactory. Here, we assessed the serum levels of secreted frizzled related protein 4 (sFRP-4) for diagnosing HCC in patients infected with chronic hepatitis B (CHB).
METHODS: In 272 patients with CHB enrolled, 142 were patients with HCC. Thirty-three healthy subjects were recruited as healthy controls. The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients (8 CHB-related HCC patients, 7 CHB patients) for serum markers. Four markers and one candidate marker were assessed in the test group and validation group, respectively.
RESULTS: Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients (P<0.05). Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group (79.7 vs 41.3 ng/mL; P<0.001) and validation group (89.0 vs 39.0 ng/mL; P<0.001). Areas under the Receiver Operating Characteristic curves (AUCs) for alpha-fetoprotein (AFP) and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 (a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL) and AFP (a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL) showed better performance for diagnosing HCC (a sensitivity of 79.2% and a specificity of 95.3%). The AUC for combined sFRP-4 and AFP increased to 0.941 (95% CI: 0.908-0.975), and similar results were seen in the validation group.
CONCLUSION: sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.

BACKGROUND: Prothymosin α (PTMA) is a nuclear oncoprotein-transcription factor essential for cell cycle progression and proliferation. PTMA was overexpressed in several human malignancies including hepatocellular carcinoma (HCC). However, the prognostic significance of PTMA protein expression in HCC remains unclear. In the present study, we evaluated PTMA protein expression by immunohistochemistry in order to elucidate the prognostic roles of PTMA in HCC patients.
METHODS: By immunohistochemistry, we investigated the expression of PTMA protein in tumor tissue from 226 HCC patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 120 months.
RESULTS: PTMA expression was observed in 162 (71.7%) of the 226 HCC patients and was significantly associated with higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T-stage, and lower albumin level. PTMA expression was an independent predictor of early recurrence (P=0.001). PTMA expression showed an unfavorable influence on recurrence-free survival (RFS) (P<0.001). Subgroup analysis showed that among patients with tumor size ≤5.0 cm (140 patients), patients at AJCC T-stage 1 (95 patients) and patients with α-fetoprotein ≤20 ng/mL (83 patients), the differences in RFS between PTMA-positive and PTMA-negative groups were also statistically significant (P=0.017, P=0.002 and P=0.002, respectively). In addition, PTMA expression was an independent predictor of shorter RFS (P=0.011). PTMA expression showed an unfavorable influence on overall survival (P=0.014), but was not an independent predictor of shorter overall survival (P=0.161).
CONCLUSIONS: PTMA protein expression might be a novel predictor of early recurrence and RFS in HCC patients, even those at early stage or with α-fetoprotein-negative after curative hepatectomy. PTMA could be used as an immunohistochemical biomarker to detect patients with a high risk of recurrence.

BACKGROUND: Early recurrence of hepatocellular carcinoma (HCC) is associated with worse prognosis after liver resection. This study aimed to investigate the prognostic value of common liver enzyme markers in HCC early recurrence after curative hepatectomy and to establish a simple predictive model for HCC early recurrence.
METHODS: A total of 200 patients who had undergone curative resection for HCC were retrospectively analyzed. The patients were divided into early recurrence (within 2 years) and non-early recurrence groups. Demographical characteristics, preoperative liver function parameters, surgical factors and tumor related factors of the patients were assessed by univariate analysis to identify potential significant predictors for early recurrence after resection of HCC. Parameters with statistical significance were entered into a Cox proportional hazard model to find independent risk factors. Receiver operating characteristic analysis was done to determine optimal cut-off values and the number of combined factors in multi-factor predictive model.
RESULTS: Of 13 potential risk factors for early recurrence identified by univariate analysis, high lactate dehydrogenase (LDH>206 U/L, HR=1.711, P=0.006), high aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AST/ALT>0.96, HR=1.769, P=0.006), elevated alpha-fetoprotein (AFP>8.6 ng/mL, HR=2.079, P=0.007), small resection margin (≤1 cm, HR=2.354, P<0.001) and advanced TNM stage (TNM III-IV, HR=2.164, P<0.001) were independent risk factors for early recurrence of HCC shown by multivariate analysis. Patients with three or more concurrent independent risk factors had significantly higher risk for early recurrence than those with low risk factors. The sensitivity and specificity of this predictive model are 53.6% and 80.7%, respectively (area under curve=0.741, 95% CI 0.674-0.800, P<0.0001).
CONCLUSIONS: Preoperative common liver enzyme markers, LDH and AST/ALT ratio, were independently associated with early recurrence of HCC. The combination of serum liver enzyme markers with AFP, resection margin and TNM stage better predicted early recurrence of HCC after curative resection in a simple multi-factor model.

BACKGROUND: Cell therapy has been promising for various diseases. We investigated whether transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) has any therapeutic effects on D-galactosamine/lipopolysaccharide (GalN/LPS)-induced fulminant hepatic failure in mice.
METHODS: hUCMSCs isolated from human umbilical cord were cultured and transplanted via the tail vein into severe combined immune deficiency mice with GalN/LPS-induced fulminant hepatic failure. After transplantation, the localization and differentiation of hUCMSCs in the injured livers were investigated by immunohistochemical and genetic analyses. The recovery of the injured livers was evaluated histologically. The survival rate of experimental animals was analyzed by the Kaplan-Meier method and log-rank test.
RESULTS: hUCMSCs expressed high levels of CD29, CD73, CD13, CD105 and CD90, but did not express CD31, CD79b, CD133, CD34, and CD45. Cultured hUCMSCs displayed adipogenic and osteogenic differentiation potential. Hematoxylin and eosin staining revealed that transplantation of hUCMSCs reduced hepatic necrosis and promoted liver regeneration. Transplantation of hUCMSCs prolonged the survival rate of mice with fulminant hepatic failure. Polymerase chain reaction for human alu sequences showed the presence of human cells in mouse livers. Positive staining for human albumin, human alpha-fetoprotein and human cytokeratin 18 suggested the formation of hUCMSCs-derived hepatocyte-like cells in vivo.
CONCLUSIONS: hUCMSC was a potential candidate for stem cell based therapies. After transplantation, hUCMSCs partially repaired hepatic damage induced by GalN/LPS in mice. hUCMSCs engrafted into the injured liver and differentiated into hepatocyte-like cells.

BACKGROUND: Liver ischemia reperfusion (IR) injury triggers a systemic inflammatory response and is the main cause of organ dysfunction and adverse postoperative outcomes after liver surgery. Pentoxifylline (PTX) and hypertonic saline solution (HTS) have been identified to have beneficial effects against IR injury. This study aimed to investigate if the addition of PTX to HTS is superior to HTS alone for the prevention of liver IR injury.
METHODS: Male Wistar rats were allocated into three groups. Control rats underwent 60 minutes of partial liver ischemia, HTS rats were treated with 0.4 mL/kg of intravenous 7.5% NaCl 15 minutes before reperfusion, and HPTX group were treated with 7.5% NaCl plus 25 mg/kg of PTX 15 minutes before reperfusion. Samples were collected after reperfusion for determination of ALT, AST, TNF-α, IL-6, IL-10, mitochondrial respiration, lipid peroxidation, pulmonary permeability and myeloperoxidase.
RESULTS: HPTX significantly decreased TNF-α 30 minutes after reperfusion. HPTX and HTS significantly decreased ALT, AST, IL-6, mitochondrial dysfunction and pulmonary myeloperoxidase 4 hours after reperfusion. Compared with HTS only, HPTX significantly decreased hepatic oxidative stress 4 hours after reperfusion and pulmonary permeability 4 and 12 hours after reperfusion.
CONCLUSION: This study showed that PTX added the beneficial effects of HTS on liver IR injury through decreases of hepatic oxidative stress and pulmonary permeability.

BACKGROUND: Gallbladder adenoma is a pre-cancerous neoplasm and needs surgical resection. It is difficult to differentiate adenoma from other gallbladder polyps using imaging examinations. The study aimed to illustrate characteristics of contrast-enhanced ultrasound (CEUS) and its diagnostic value in gallbladder adenoma.
METHODS: Thirty-seven patients with 39 gallbladder adenomatoid lesions (maximal diameter ≥10 mm and without metastasis) were enrolled in this study. Lesion appearances in conventional ultrasound and CEUS were documented. The imaging features were compared individually among gallbladder cholesterol polyp, gallbladder adenoma and malignant lesion.
RESULTS: Adenoma lesions showed iso-echogenicity in ultrasound, and an eccentric enhancement pattern, "fast-in and synchronous-out" contrast enhancement pattern and homogeneous at peak-time enhancement in CEUS. The homogenicity at peak-time enhancement showed the highest diagnostic ability in differentiating gallbladder adenoma from cholesterol polyps. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and Youden index were 100%, 90.9%, 92.9%, 100%, 95.8% and 0.91, respectively. The characteristic of continuous gallbladder wall shown by CEUS had the highest diagnostic ability in differentiating adenoma from malignant lesion (100%, 86.7%, 86.7%, 100%, 92.9% and 0.87, respectively). The characteristic of the eccentric enhancement pattern had the highest diagnostic ability in differentiating adenoma from cholesterol polyp and malignant lesion, with corresponding indices of 69.2%, 88.5%, 75.0%, 85.2%, 82.1% and 0.58, respectively.
CONCLUSIONS: CEUS is valuable in differentiating gallbladder adenoma from other gallbladder polyps (≥10 mm in diameter). Homogeneous echogenicity on peak-time enhancement, a continuous gallbladder wall, and the eccentric enhancement pattern are important indicators of gallbladder adenoma on CEUS.

BACKGROUND: 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown.
METHODS: Lesions of PanIN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozygous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR amplification and direct sequencing.
RESULTS: DMBA implantation in the 40 rats induced 26 PanINs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions.
CONCLUSION: Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.

BACKGROUND: Pancreatic stellate cells (PSCs) play a critical role in the development of pancreatic fibrosis. In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory effects of adipose-derived stem cells (ADSCs) on activation and proliferation of PSCs.
METHODS: Pancreatic tissue was obtained from Sprague-Dawley rats for PSCs isolation. Transwell cell cultures were adopted for co-culture of ADSCs and PSCs. PSCs proliferation and apoptosis were determined using CCK-8 and flow cytometry, respectively. α-SMA expressions were analyzed using Western blotting. The levels of cytokines [nerve growth factor (NGF), interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1)] in conditioned medium were detected by ELISA. Gene expression (MMP-2, MMP-9 and TIMP-1) was analyzed using qRT-PCR.
RESULTS: This method produced 17.6±6.5×10³ cells per gram of the body weight with a purity of 90%-95% and a viability of 92%-97%. Co-culture of PSCs with ADSCs significantly inhibited PSCs proliferation and induced PSCs apoptosis. Moreover, α-SMA expression was significantly reduced in PSCs+ADSCs compared with that in PSC-only cultures, while expression of fibrinolytic proteins (e.g., MMP-2 and MMP-9) was up-regulated and anti-fibrinolytic protein (TIMP-1) was down-regulated. In addition, NGF expression was up-regulated, but IL-10 and TGF-β1 expressions were down-regulated in the co-culture conditioned medium compared with those in the PSC-only culture medium.
CONCLUSIONS: This study provided an easy and reliable technique to isolate PSCs. The data demonstrated the inhibitory effects of ADSCs on the activation and proliferation of PSCs in vitro.